In the past 2 decades, interest in links between autoimmunity and cancer have escalated. Systemic lupus erythematosus (SLE), the prototype autoimmune disease, is the 2nd most common autoimmune disorder occurring in childbearing women. Previous studies were inconclusive when evaluating the potential relationship between SLE and cancer; however, our investigative team conducted a cohort study of 7200+ SLE patients with 59,000+ follow-up years, where results confirm that all cancers (Standardized Incidence Ratio, [SIR] 1.2, 95% Confidence Interval, [CI] 1.1, 1.4) and certain cancers, particularly hematologic (SIR 3.0, 95% CI 2.3, 3.8), occur more frequently than expected in SLE. Further, our cohort study shows the highest point estimates or SIRs occur in the 1st year of SLE, suggesting that cancer risk is not completely explained by the cumulative dose of immunosuppressive drug (ISD) exposure. Therefore, elucidation of the role of ISDs with respect to cancer risk in SLE is needed and the logical next step is to test hypotheses exploring susceptibility to cancer in SLE with and without exposures to ISDs. We are proposing to conduct a case-cohort study (a flexible and efficient varation of the classical nested case-control design), within the context of our unique international multi-center cohort study, to determine whether ISDs (azathiopdne, cyclophosphamide, methotrexate, or cyclosporin) influence cancer risk, specifically targeting hematologic malignancies, in SLE. In the primary analysis, modified Cox proportional hazards regression will be used to calculate the risk ratio for hematologic cancer development after exposure to ISDs in a model that controls for other medication use, age, sex, and SLE disease duration and damage. In secondary analyses, we will examine the potential role of other clinical factors, such as secondary Sjogren's syndrome or effect modifiers, such as smoking. If certain ISDs are linked to cancer risk, prescribing patterns may change. This study may also provide new information about potential links between cancer and autoimmunity.